Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the predominant pathologic findings are demyelination accompanied by disruption of underlying axons (Trapp et al., New Engl. J. Med. 338:278–285, 1998; Prineas, J. W., “Pathology of Multiple Sclerosis” in: Cook S D, ed. Handbook of Multiple Sclerosis. New York: Marcel Dekker, Inc, 1990:187–215). The disease affects young adults who usually present with a relapsing, remitting pattern of neurologic involvement and progress to a chronic phase with increasing difficulty in ambulation and coordination. The etiology of MS is not known, but there is considerable indirect evidence that argues for the role of an infectious agent(s) in the pathogenesis of the disease. Epidemiological studies strongly suggest that a CNS infection in early childhood is a key factor in the development of MS (Kurtzke, Clin. Microbiol. Rev. 6:382–427, 1993). Viral infections have long been thought to play a possible role in the pathogenesis of MS because viruses are known to cause demyelinating disease in experimental animals, often present clinically with relapsing, remitting symptoms, and can cause disease with long periods of latency (Cook and Dowling, Neurology 30:80–91, 1980; Johnson, R. T.,. Viral infections of the Nervous System. New York: Raven Press, 1982). Studies to date, however, have failed to identify any virus as playing a major role in MS, although activated human herpes virus 6 (HHV-6) has been identified recently in brains of MS patients (Sanders et al., J. Neurovirol. 2:249–258, 1996; Challoner et al., Proc. Natl. Acad. Sci. USA 92:7440–7444, 1995; Merelli, J. Neurol. 244:450–454, 1997). Although an immune response to this virus is seen during acute exacerbations, the role of HHV-6 infection in MS remains unclear (Soldan et al., Nature Med. 3:1394–1397, 1997).
Current opinion thus favors MS to be an autoimmune disease directed against self neural antigens (Martin et al., Annu. Rev. Immunol. 10:153–169, 1992). To reconcile the role of environment in the pathogenesis of MS as well as the absence of an identifiable infectious pathogen, it is believed that infectious agents may act to trigger an autoimmune process. Such an autoimmune response may result from structural similarities between an infectious agent and neural antigens (antigenic mimicry) or from an expansion of self autoreactive T cell clones in response to bacterial or viral superantigens (Brocke et al., Nature 65:642–646, 1993; Jahnke et al., Science 229:282–284, 1985; Marrack and Kappler, Science 248:325–329, 1998; Oldstone, J. Autoimmun. 2(S):187–194, 1989). Evidence that MS is a disease mediated by T cells that recognize neural antigens has been hard to justify, since measures directed at either eliminating or reducing helper T cell function have not changed the natural history of MS (Sriram and Rodriguez, Neurology 48:469–473, 1997). Improved methods of diagnosing MS would facilitate identification of treatable pathogens and expedite commencement of treatment.
Over the last few years, therapy with β-IFN has emerged as a means of reducing the morbidity of MS. Both β-IFNs (β-1a and β-1b) reduce the number of clinical relapses and slow the progression of the disease. In addition, magnetic resonance imaging (MRI) studies demonstrate a decrease in the number of new inflammatory cerebral lesions in patients receiving β-IFN. Although β-IFN was introduced as a therapeutic agent for MS based on its anti-viral properties, the reasons for the therapeutic benefit of β-IFN for MS remain unclear. Thus far, no viral agent has been consistently found to be associated with MS.